The general goal of this proposal is to develop a new synthetic methodology where high yielding photochemical key reactions are incorporated into a diversity-oriented split-and-pool combinatorial synthesis. Photochemistry offers a range of spectacular skeletal transformations, yet their utilization in high throughput synthetic methods is insignificant. We aim to develop a new synthetic methodology for rapid access to topologically diverse polycyclic scaffolds decorated by various functional groups and carbo/heterocyclic pendants, rigidly or semi-rigidly held in a unique spatial configuration by this core framework. Expeditious access to such topologically diverse scaffolds will be realized via key photochemical steps and their combination with ground state reactions, most prominently - the recently discovered synthetic sequence based on photoprotolytic oxametathesis. Achieving a well-defined three-dimensional relationship within an assortment of functional groups and/or heterocyclic moieties is central to synthetic medicinal chemistry. A broad objective is to generate potential pharmacophores by systematically sampling the chemical space with diversified core structures augmented with a range of peripheral functionalities. From the high throughput chemistry standpoint this task can only be achieved with a diverse set of distinctive core scaffolds suspending a variety of functional pendants in a unique 3D pattern. Our photoprotolytic oxametathesis allows for the generation of topologically unprecedented polycyclic acetal scaffolds, rigidly displaying a variety of heterocycles in a well-defined spatial arrangement. Critical for the split-and-pool implementation of this synthetic strategy is the fact that the photoprotolytic sequence offers nearly quantitative yields. PUBLIC HEALTH RELEVANCE: Photochemical reactions initiated by light hold unparalleled promise for building unusual molecular frameworks and offer expeditious access to difficult synthetic targets. Yet, with the exception of a few landmark syntheses, synthetic organic photochemistry remains underutilized by synthetic organic chemists. This is especially true for diversity-oriented synthesis (DOS) and its split-and-pool implementation, which are most relevant to high-throughput synthesis of small molecules and discovery of new promising therapeutic agents. We are developing novel synthetic methodologies, enabling us to gain expeditious access to a massive number of new drug-like molecules, which will be available for biological screening. Not unimportant is the fact that photochemical steps use light as a reagent, and therefore could be environmentally friendly.